Dataset Information

TIP110/p110nrb/SART3/p110 regulation of hematopoiesis through CMYC.

ABSTRACT: Intracellular factors are involved in and essential for hematopoiesis. HIV-1 Tat-interacting protein of 110 kDa (TIP110; p110(nrb)/SART3/p110) is an RNA-binding nuclear protein implicated in the regulation of HIV-1 gene and host gene transcription, pre-mRNA splicing, and cancer immunology. In the present study, we demonstrate a role for TIP110 in the regulation of hematopoiesis. TIP110 was expressed in human CD34(+) cells and decreased with differentiation of CD34(+) cells. TIP110 mRNA was also expressed in phenotyped mouse marrow hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs). Using TIP110 transgenic (TIP110(TG)) and haploinsufficient (TIP110(+/-)) mice, we found that increased TIP110 expression enhanced HPC numbers, survival, and cell cycling, whereas decreased TIP110 expression had the opposite effects. Moreover, TIP110(+/-) bone marrow HPCs responded more effectively, and TIP110(TG) HPCs less effectively, than those of wild-type control mice to recovery from the cell-cycle-active drug 5-fluorouracil (5-FU). Unexplained sex differences were noted in HSC competitive repopulating ability, but not HPC numbers, in TIP110(TG) mice. Intracellularly, TIP110 regulated CMYC and GATA2 expression at the transcriptional level, and TIP110 and CMYC reciprocally regulated the expression of each other. These results demonstrate a role for TIP110 in the regulation of hematopoiesis, effects that are likely linked to TIP110 regulation of CMYC.

SUBMITTER: Liu Y

PROVIDER: S-EPMC3110023 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

TIP110/p110nrb/SART3/p110 regulation of hematopoiesis through CMYC.

Liu Ying Y Timani Khalid K Mantel Charlie C Fan Yan Y Hangoc Giao G Cooper Scott S He Johnny J JJ Broxmeyer Hal E HE

Blood 20110329 21

Intracellular factors are involved in and essential for hematopoiesis. HIV-1 Tat-interacting protein of 110 kDa (TIP110; p110(nrb)/SART3/p110) is an RNA-binding nuclear protein implicated in the regulation of HIV-1 gene and host gene transcription, pre-mRNA splicing, and cancer immunology. In the present study, we demonstrate a role for TIP110 in the regulation of hematopoiesis. TIP110 was expressed in human CD34(+) cells and decreased with differentiation of CD34(+) cells. TIP110 mRNA was also ...[more]

PMID: 21447833

Similar Datasets

Project description:BACKGROUND:Ovarian cancer is one of the most significant malignancies in the western world. Studies showed that Ovarian cancers tend to grow resistance to cisplatin treatment. Therefore, new approaches are needed in ovarian cancer treatment. Kaempferol is a dietary flavonoid that is widely distributed in fruits and vegetables, and epidemiology studies have revealed a protective effect of kaempferol against ovarian cancer risk. Our early studies also found that kaempferol is effective in reducing vascular endothelial growth factor (VEGF) expression in ovarian cancer cells. In this study, we investigated kaempferol's effects on sensitizing ovarian cancer cell growth in response to cisplatin treatment. RESULTS:Ten chemicals were screened for sensitizing OVCAR-3 ovarian cancer cell growth in response to cisplatin treatment. For kaempferol, which shows a significant synergistic interaction with cisplatin, expression of ABCC1, ABCC5, ABCC6, NFkB1, cMyc, and CDKN1A genes was further examined. For cisplatin/kaempferol treatments on OVCAR-3 cancer cells, the mRNA levels of ABCC1, ABCC5, and NFkB1 did not change. However, significant inhibition of ABCC6 and cMyc mRNA levels was observed for the cisplatin/kaempferol combined treatment. The CDKN1A mRNA levels were significantly up-regulated by cisplatin/kaempferol treatment. A plot of CDKN1A mRNA levels against that of cMyc gene further revealed a reverse, linear relationship, proving cMyc's regulation on CDKN1A gene expressions. Our work found that kaempferol works synergistically with cisplatin in inhibiting ovarian cancer cell viability, and their inhibition on cell viabilities was induced through inhibiting ABCC6 and cMyc gene transcription. Apoptosis assay showed the addition of 20 muM kaempferol to the cisplatin treatment induces the apoptosis of the cancer cells. CONCLUSIONS:Kaempferol enhances the effect of cisplatin through down regulation of cMyc in promoting apoptosis of ovarian cancer cells. As a dietary component, kaempferol sensitizes ovarian cancer cells to cisplatin treatment and deserves further studies for possible applications in chemotherapy of ovarian cancers.

Project description:Cholangiocarcinoma (CCA) is a malignant cancer with an unknown etiology and an unfavorable prognosis. Most patients are diagnosed at an advanced stage, thus making it essential to find novel curative targets for CCA. Metabolic reprogramming of the tumor cells includes metabolic abnormalities in glucose (known as the Warburg effect) and other substances such as amino acids and fats. Metabolic reprogramming produces anti-oxidant substances, reduces tumor oxidative stress, and finally promotes the proliferation of tumors. There is increasing evidence to imply that SIRT2, a histone deacetylase, and its downstream target cMYC, play metabolic regulatory roles in tumor cells. However, the role of the SIRT2/cMYC pathway in CCA is unclear. To assess the metabolic reprogramming function of the SIRT2/cMYC pathway in CCA and to determine the downstream targets as well as evaluate the therapeutic effect, the CCA RNA-Seq data were downloaded from the TCGA database. Differentially expressed genes were confirmed and KEGG pathway enrichment analysis was performed. Overall, 48 paired CCA samples were collected and subjected to immunohistochemical detection, and the clinical characteristics of participants were summarized. The CCA cells were suppressed or overexpressed with different downstream targets of SIRT2 and then subjected to apoptosis, immunoblotting, seahorse, and metabolites tracing analysis. In vivo experiments were also performed. We found that the SIRT2/cMYC pathway contributed to the proliferation of CCA cells and confirmed that the downstream target is PHDA1 and the serine synthesis pathway. The up-regulated SIRT2 and cMYC levels resulted in low levels of mitochondrial oxidative phosphorylation and increased conversion of glucose to serine and led to poor patient survival. The highly active SIRT2/cMYC pathway up-regulated the serine synthesis pathway pyruvate and increased antioxidant production, thus consequently protecting the CCA cells from oxidative stress-induced apoptosis. Our data revealed that the SIRT2/cMYC pathway plays a critical role in transforming glucose oxidative metabolism to serine anabolic metabolism, thus providing antioxidants for stress resistance. SIRT2/cMYC-induced metabolic reprogramming may represent a new therapeutic target for treating CCA.

Project description:Human blood develops from self-renewing hematopoietic stem cells to terminal lineages and necessitates regulator and effector gene expression changes; each cell type specifically expresses a subset of genes to carry out a specific function. Gene expression changes coincide with histone modification, histone variant deposition, and recruitment of transcription-related enzymes to specific genetic loci. Transcriptional regulation has been mostly studied using in vitro systems while epigenetic changes occurring during in vivo development remain poorly understood.By integrating previously published and novel global expression profiles from human CD34+/CD133+ hematopoietic stem and progenitor cells (HSPCs), in vivo differentiated human CD4+ T-cells and CD19+ B-cells, and in vitro differentiated CD36+ erythrocyte precursors, we identified hundreds of transcripts specifically expressed in each cell type. To relate concurrent epigenomic changes to expression, we examined genome-wide distributions of H3K4me1, H3K4me3, H3K27me1, H3K27me3, histone variant H2A.Z, ATP-dependent chromatin remodeler BRG1, and RNA Polymerase II in these cell types, as well as embryonic stem cells. These datasets revealed that numerous differentiation genes are primed for subsequent downstream expression by BRG1 and PolII binding in HSPCs, as well as the bivalent H3K4me3 and H3K27me3 modifications in the HSPCs prior to their expression in downstream, differentiated cell types; much HSPC bivalency is retained from embryonic stem cells. After differentiation, bivalency resolves to active chromatin configuration in the specific lineage, while it remains in parallel differentiated lineages. PolII and BRG1 are lost in closer lineages; bivalency resolves to silent monovalency in more distant lineages. Correlation of expression with epigenomic changes predicts tens of thousands of potential common and tissue-specific enhancers, which may contribute to expression patterns and differentiation pathways.Several crucial lineage factors are bivalently prepared for their eventual expression or repression. Bivalency is not only resolved during differentiation but is also established in a step-wise manner in differentiated cell types. We note a progressive, specific silencing of alternate lineage genes in certain cell types coinciding with H3K27me3 enrichment, though expression silencing is maintained in its absence. Globally, the expression of type-specific genes across many cell types correlates strongly with their epigenetic profiles. These epigenomic data appear useful for further understanding mechanisms of differentiation and function of human blood lineages.

Dataset Information

TIP110/p110nrb/SART3/p110 regulation of hematopoiesis through CMYC.

Publications

TIP110/p110nrb/SART3/p110 regulation of hematopoiesis through CMYC.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets